Cardiovascular disease (CVD) is the leading cause of death world-wide. High levels of serum total cholesterol (TC) and triglycerides (TGs) are well-established risk factors of CVD. The prevalence of dyslipidemia differs between populations, the Amerindian origin populations, i.e. Latinos, exhibiting the highest susceptibility. Latinos, who have been underrepresented in genomic studies despite their high predisposition to CVD, are the most rapidly growing population group in the U.S. Alone in Los Angeles, the most recent U.S Census Bureau data from 2010 show that 49% of the Los Angeles county population are Latinos and 77% of California Latinos originate from Mexico. We hypothesize that there are population-based variants and genes that contribute to the increased susceptibility of dyslipidemia in Latinos. Our Specific aims are targeted to identify population-specific lipid genes in Mexicans utilizing a novel cross-population allele-screen (CPAS) approach that identifies variants present in the Amerindian origin part of the Mexican genomes and using exome sequencing; and as well as using a new multilayer genomic approach of a mixed model that can incorporate the presence of the admixed ancestry. In Specific aim 1, we will fine the regions of the 13 Amerindian-specific triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) variants that we identified using our original CPAS approach in order to identify the full spectrum and different types of lipid variants. Importantly, 4 of these variants reside in genes/genomic loc not implicated for lipids and CVD in other populations before. We also demonstrated that two of the key TG Amerindian regions had undergone a recent positive selection in Mexicans measured by extended linkage disequilibrium (LD) of the haplotypes surrounding the associated variants, suggesting that a high serum lipid level was a key to Amerindian survival historically. We hypothesize that these once advantageous Amerindian variants now increase the risk of dyslipidemia in Latinos, likely due to the recent adoption of Western diet. We will test this hypothesis by performing hypothesis-based diet studies in variant carriers. We will also screen for additional Mexican-specific lipid genes and rare and low frequency dyslipidemia variants using exome sequencing. Our Specific aim 2 is targeted to identifying and understanding dynamic adipose regulome changes, integrative factors, and multiple pathways leading to dyslipidemia and CVD in Mexicans. To the best of our knowledge, no regulome or multilayer genomics studies of dyslipidemia and CVD have been performed in Latinos so far. In Specific aim 2, we hypothesize that systematic examination of genetic variation in transcriptomic and epigenomic regulation will elucidate the molecular basis of the regulome alterations leading to the high predisposition of dyslipidemia in Mexicans. An epigenomic analysis is warranted as the constantly increasing prevalence of hypertriglyceridemia suggests that epigenetic and environmental factors also play a role in the pathogenesis of this CVD risk factor. Our genomic and epigenomic studies tailored to admixed populations hold great potential to advance population-based diagnosis, prevention, and treatment of CVD, ultimately guiding us towards personalized medicine in Latinos.